Liver fibrosis (LF)/cirrhosis is a major global health problem and one of the leading causes of morbidity and mortality in the world. Alcohol abuse is one of the most common causes of liver fibrosis/cirrhosis in developed Western countries, accounting for more than 50% of cirrhosis cases. At present, there is no effective treatment for LF. Alcoholic liver fibrogenesis evolves from an imbalance between cytokines and hepatic stellate cell (HSC) activation and transdifferentiation into myofibroblasts. Attenuating these profibrotic mechanisms is an important step towards developing new therapeutic interventions for LF. Our long-term goal is to elucidate the regulatory mechanisms in LF pathology as a necessary prerequisite for the development of therapeutic agents that will minimize or reverse fibrosis. CTGF/CCN2 (connective tissue growth factor, CTGF) is a stable, profibrotic protein that promotes HSC adhesion, proliferation, locomotion, and collagen production. In a fibrotic liver, CTGF/CCN2 is produced by HSCs, fibroblasts, myofibroblasts, endothelial cells, and bile duct epithelial cells. CTGF/CCN2 expression promotes LF. CTGF administration significantly upregulates type I collagen synthesis and promotes fibrosis by mediating the ability of transforming growth factor ? (TGF-?) to induce excess extracellular matrix (ECM) production. Following stimulation by the fibrotic inflammatory mediator TGF-?, CTGF/CCN2 expression in cultured HSCs is enhanced. Loss of CTGF/CCN2 in fibroblasts results in decreased collagen deposition and resistance to chemically induced skin fibrosis. Knockout of CTGF/CCN2 prevents LF, thus modulation of its activity/expression represents a novel therapeutic target in this disease. However, factors that regulate CTGF/CCN2 mRNA expression and prolonged stability in liver fibrosis are unknown. Tristetraprolin (TTP) is an mRNA-binding protein that destabilizes mRNAs, leading to reduced protein expression. However, the link between TTP expression and stability of CTGF is unknown. TTP is highly expressed only in the liver compared to other tissues; moreover, significant downregulation of TTP is evident in hepatitis B virus (HBV)-associated cirrhosis. However, the role of TTP in controlling the expression of profibrotic CTGF/CCN2 has not been explored. We have developed a novel hypothesis that TTP functions as an mRNA destabilizer of CGF/CCN2 expression and that loss of TTP leads to alcohol-induced LF by hepatic stellate cell (HSC) activation and transdifferentiation into myofibroblasts. To test this hypothesis, the following specific aims are proposed: Aim #1: Define the role of TTP as a negative regulator of CTGF/CCN2 expression and concurrent HSC differentiation by assessing gain/loss of TTP in vitro. Aim #2: To determine whether TTP suppression is critical for alcoholic- induced fibrosis and further examine whether TTP-deficiency exacerbates alcohol-induced fibrosis. The outcome of this study will be a fundamental, ground-breaking understanding of the mechanisms that control the expression of the profibrotic molecule CTGF/CCN2 in alcoholic LF. This will have a significant impact on the development of novel therapies for alcoholic liver fibrosis.